The invention concerns substituted glutarimides having the general formula I 
their production and their use in medicaments.
Autoimmune diseases arise as a result of a reactivity of the immune system against structures or components occurring naturally in the body. As part of this process, the normally existing tolerance towards the body""s own tissue lapses. In addition to antibodies, T-lymphocytes and monocytes/macrophages in particular play a significant role in the pathogenesis of the various autoimmune diseases. Activated monocytes and/or macrophages secrete a number of different proinflammatory mediators that are directly or indirectly responsible for destroying the tissue affected by the autoimmune disease. The activation of monocytes/macrophages occurs either in the interaction with T-lymphocytes or via bacterial products such as lipopolysaccharide (LPS).
IL-12 is a heterodimeric molecule consisting of a covalently bonded p35 and p40 chain. The molecule is formed by antigen-presenting cells (monocytes/macrophages, dendritic cells, B-lymphocytes). The formation of 1L-12 by monocytes/macrophages is triggered either by various microbial products such as LPS, lipopeptides, bacterial DNA or in the interaction with activated T-lymphocytes (Trinchieri, 1995, Ann. Rev. Immunol. 13: 251). IL-12 has a central immunoregulatory significance and is responsible for the development of proinflammatory TH1 reactivities. The presence of a TH1 immune reaction against self-antigens leads to the occurrence of serious diseases.
The significance of inflammatory cytokines such as IL-12 for the development and course of inflammations and autoimmune diseases has been clearly documented by numerous animal experimental and preliminary clinical trials. The pathophysiological importance of IL-12 has been demonstrated in various animal models for diseases such as rheumatoid arthritis, multiple sclerosis, diabetes mellitus and inflammatory diseases of the intestines, skin and mucous membranes (Trembleau et al., 1995, Immunol. Today 16: 383; Muller et al., 1995, J. Immunol. 155: 4661; Neurath et al., 1995, J. Exp. Med. 182: 1281; Segal et al., 1998, J. Exp. Med. 187: 537; Powrie et al., 1995, Immunity 3: 171; Rudolphi et al., 1996, Eur. J. Immunol. 26: 1156; Bregenholt et al., 1998, Eur. J. Immunol. 28: 379). Application of IL-12 could trigger the relevant disease and neutralisation of endogenous IL-12 led to the course of the disease being moderated, or even the cure of the animals. The use of antibodies against IL-12 in humans is imminent.
It can be said in summary that an excess of IL-12 conditions the pathophysiology of a number of inflammatory diseases. Attempts to normalize the IL-12 level therefore have great therapeutic potential.
IL-12 is also involved in regulating the survival of cells. Uncontrolled cell growth is regulated by apoptosis (programmed cell death) amongst other things. Using T-lymphocytes it has been shown that IL-12 has an anti-apoptotic action and promotes the survival of T-cells (Clerici et al., 1994, Proc. Natl. Acad. Sci. USA 91: 11811; Estaquier et al., 1995, J. Exp. Med. 182: 1759). A local overproduction of IL-12 can therefore contribute to the survival of tumour cells.
Inhibitors of IL-12 formation therefore possess great therapeutic potential.
One potential inhibitor of IL-12 formation is the known active agent thalidomide (Journal of Immunology 159 (10), 5157-5161 (1997)).
U.S. Pat. No. 5,114,937 describes renin-inhibiting peptide derivatives, the carboxamide groups in which are replaced by their isosteres. The compounds are suitable for the treatment of renin-associated hypertension, congestive heart failure, hyperaldosteronism, glaucoma and diseases caused by the retroviruses HTLV-I, -II and -III.
DE 198 43 793 describes substituted benzamides with immunomodulatory properties in which the ring-containing structural parts of the molecule are linked together by an amide bond. The disadvantage of the amide bond is its susceptibility to hydrolysis with an accompanying loss of action for the compound.
The object of the invention was therefore to develop new immunomodulators that are suitable for the treatment and/or prophylaxis of diseases caused by formation of the proinflammatory cytokine IL-12 and that at the same time display an improved hydrolytic stability.
It has now been discovered that substituted glutarimides satisfy the above requirements.
The invention accordingly provides substituted glutarimides having the formula I 
in which X denotes a group having the formula CH2xe2x80x94NH or Sxe2x80x94CH2,
R1 stands for a carboxyl group; an ester group having the formula COOR5 in which R5 denotes an alkyl group (straight-chain or branched) with 1 to 6 carbon atoms or a benzyl radical; or an amide group having the formula CONR6R7, in which R6 and R7 are the same or different and represent hydrogen, an alkyl group (straight-chain or branched) with 1 to 6 Carbon atems (optionally substituted with the radical COOR5 and/or a phenyl group), a phenyl radical or taken together with the N atom represent a hydrazide group, a pyrrolidine, piperidine or morpholine ring or stand for an amino group substituted with the radical CH(xe2x95x90O) or COR5, in which R5 is as defined above, and
R2 stands for hydrogen, an amino or nitro group, and enantiomers, mixtures of enantiomers, racemates, diastereomers or mixtures of diastereomers thereof in the form of their bases or salts with physiologically compatible acids.
The following substituted glutarimides are particularly preferred:
2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl]benzoic acid,
2-[(3R)-(2,6-dioxopiperidin-3-ylamino)methyl]benzoic acid,
2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl]-N,N-diethylbenzamide,
(3S)-[2-morpholine-4-carbonyl)benzylamino]piperidine-2,6-dione,
{2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl]benzoylamino}methyl acetate,
2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl]benzamide,
2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl]-N-ethyl benzamide,
(3S)-[2-pyrrolidine-1-carbonyl)benzylamino]piperidine-2,6-dione,
2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl]benzoic acid hydrazide,
2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl]-N-phenyl benzamide,
2-[(3R)-(2,6-dioxopiperidin-3-ylamino)methyl]-N-phenyl benzamide,
2-[(3R)-(2,6-dioxopiperidin-3-ylamino)methyl]-N,N-diethyl benzamide,
2-[(3R)-(2,6-dioxopiperidin-3-ylamino)methyl]benzamide,
2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl]methyl benzoate,
2-[(3S)-(2,6-dioxopiperidin-3-ylamino)methyl]benzyl benzoate,
2-(2,6-dioxopiperidin-3-yl methyl sulfanyl) methyl benzoate,
N-{2-[2,6-dioxopiperidin-3-ylamino)methyl]phenyl}acetamide,
N-{2-[2,6-dioxopiperidin-3-ylamino)methyl]phenyl}formamide,
3-(2,6-dioxopiperidin-3-yl methyl sulfanyl)-6-nitro methylbenzoate, and
2-amino-5-(2,6-dioxopiperidin-3-yl methyl sulfanyl) methyl benzoate.
The present invention also provides methods for the production of compounds according to the invention having the general formula I.
Compounds having the general formula I can be obtained by cyclizing glutaric acid derivatives having the general formula II, 
in which X, R1 and R2 have the same meaning as defined above for formula I, A stands for OH, B for NH2 or NHOH, or vice versa, in the presence of activating reagents such as carbonyl diimidazole. If X in the compound having the formula I denotes a CH2xe2x80x94NH group, cyclization is preferably performed with compounds having the formula II, in which the NH function is present in protected form, for example with a benzyl oxycarbonyl group, which is then removed at a temperature of between 20 and 40 xc2x0 C., e.g. with a solution of hydrogen bromide in acetic acid.
Heating a compound of formula II in which A and B both stand for OH in acetic anhydride, first produces a cyclization to the cyclic anhydride, from which the compound having formula I is obtained by heating with urea or another nitrogen source.
Compounds having the general formula I can also be produced from lactams having the general formula III, 
in which R1, R2 and X have the same meanings as defined above for formula I, by oxidizing compound III to an imide, preferably with m-chloroperbenzoic acid or ruthenium(IV) oxide/sodium periodate.
Compounds having the formula I, in which X stands for the CH2xe2x80x94NH group, can also be obtained by alkylating xcex1-aminoglutarimides having the general formula IV, 
with compounds having the general formula V, 
in which R1 and R2 have the same meanings as above and Y stands for a chlorine, bromine or iodine atom or a toluene-4-sulfonate radical.
Compounds in which X stands for the CH2xe2x80x94NH group can also be obtained by reductive amination from compounds having the general formulae VI and IV, in which R1 and R2 have the same meanings as above. 
Sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, the borane-pyridine complex or catalytically excited hydrogen is preferably used as the reducing agent.
Compounds having the formula I where X is CH2xe2x80x94NH can also be obtained by alkylating a compound having the general formula VII, 
in which R1 and R2 have the same meanings as above, with xcex1-bromoglutarimide having the general formula VIII 
Compounds having the general formula I, in which X stands for an Sxe2x80x94CH2 group, can be obtained by adding a mercaptan having the general formula X 
to 3-methylene glutarimide having the general formula IX 
The reaction is preferably performed in solvents such as acetonitrile or toluene with addition of tertiary amines such as triethylamine or diisopropyl ethylamine at temperatures of 80 to 110 xc2x0 C.
Compounds having the formula I, in which R2 stands for an amino group, can generally be obtained by reduction of compounds having the formula I where R2xe2x95x90NO2. The reduction is performed, for example, by catalytically excited hydrogen in acid-containing organic solvents such as ethyl acetate, whereby palladium catalysts are preferably used. Alternatively, the reduction can be performed with metals such as tin or iron in acid solution.
The compounds according to the invention possess immunomodulatory activity which is demonstrated by an inhibition of the production of IL-12 by LPS-activated monocytes. In comparison to compounds that have already been proposed, they also demonstrate an improved hydrolytic stability. They are suitable for the treatment and/or prophylaxis of inflammation and autoimmune diseases and also of haematological/oncological diseases.
Accordingly, the present invention also includes methods and pharmaceutical compositions for the treatment of these diseases. The method according to the invention comprises administering to a mammal, such as a human, in need thereof, an effective amount of a suitable pharmaceutical composition comprising a substituted glutarimide of the invention.
The above groups of diseases include, amongst others, inflammations of the skin (e.g. atopic dermatitis, psoriasis, eczema), inflammations of the respiratory tracts (e.g. bronchitis, pneumonia, bronchial asthma, ARDS (adult respiratory distress syndrome), sarcoidosis, silicosis/fibrosis), inflammations of the gastrointestinal tract (e.g. gastroduodenal ulcers, Crohn""s disease, ulcerative colitis), and diseases such as hepatitis, pancreatitis, appendicitis, peritonitis, nephritis, aphthosis, conjunctivitis, keratitis, uveitis, and rhinitis.
The autoimmune diseases include, for example, arthritic diseases (e.g. rheumatoid arthritis, HLA-B27-associated diseases), Behcet""s disease, and multiple sclerosis, juvenile diabetes or lupus erythematosus.
Further indications are sepsis, bacterial meningitis, cachexia, transplant rejection reactions, graft-versus-host reactions as well as reperfusion syndrome and atherosclerosis along with angiopathies (such as macula degeneration, diabetic retinopathies).
The symptoms that can be inhibited by a reduction in IL-12 also include haematological diseases such as multiple myeloma and leukaemias, along with other oncological diseases such as glioblastoma, prostate cancer and mammary cancer.
Medicaments according to the invention contain, in addition to at least one compound having the general formula I, carriers, fillers, solvents, diluents, dyestuffs and/or binders. The choice of auxiliaries and the quantities to be used depend on whether the medicament is to be administered by oral, rectal, ophthalmic (intravitreal, intracameral), nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intratracheal and epidural) means.
Preparations in the form of tablets, chewable tablets, sugar-coated tablets, capsules, granules, drops, liquids or syrups are suitable for oral administration, while solutions, suspensions, easily reconstituted dry preparations and sprays are suitable for administration by parenteral or topical means or by inhalation. Cutaneous administration forms are salves, gels, creams and pastes. Ophthalmic administration forms include drops, salves and gels. Compounds according to the invention contained in a reservoir in dissolved form, a carrier film or a plaster, optionally with the addition of skin-penetrating agents, are examples of suitable percutaneous administration forms. The compounds according to the invention can be released on a delayed basis from oral or percutaneous forms of preparation.
The amount of active agent to be administered to patients varies according to the weight of the patient, the type of administration, the indication and the severity of the disease. 1 to 150 mg/kg of at least one compound according to the invention having the formula I are conventionally administered.